For Jeffrey Chamberlain, Fighting Muscular Dystrophy on the
Genetic Level is His Life’s Work
For the millions of children and adults who suffer from
the disease, it may mean life itself
by Jeffrey Mortimer
Jeffrey S. Chamberlain
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For most researchers in the world of human biology, their work
will always be largely invisible to all except a handful of
people. Partly this is due to the complexity of biological research
today; partly it is due to the sub-microscopic nature of the
work.
But for Jeffrey S. Chamberlain, Ph.D., professor of human genetics,
who for the past decade has headed a research team in the University
of Michigan Medical School that has made several major breakthroughs
in the battle to cure muscular dystrophy, invisibility has not
been a problem. In his efforts to promote understanding and
support for his work, he has written for Parade magazine and
appeared on four different occasions on the Muscular Dystrophy
Association’s Labor Day Telethon. The Telethon, thanks
to the involvement of comedian and actor Jerry Lewis, has done
much over the years to familiarize the American public with
the terrible effects of muscular dystrophy on both children
and adults and to raise invaluable research funds for investigators
like Chamberlain. The 21-and-a-half hour event was first televised
in 1966 and now reaches more than 75 million viewers.
That science and visibility could go together was something
Chamberlain understood from an early age. Growing up in Tucson,
Arizona, where his father was an astronomer at the Kitt Peak
National Observatory, he knew as family friends many of the
popular astronauts and famous astronomers of the day. When Chamberlain’s
father was hired by NASA in the late 1960s and the family moved
to Houston, Texas, it was astronaut Buzz Aldrin’s house
that they bought.
(From Left:) Graduate
students
Dennis Hartigan-O’Connor, Susan Dombrowski, Scott Harper,
and Laura Warner conferring with Chamberlain. |
For Chamberlain, though, it was the mystery of cells rather
than the mystery of the stars and planets, that drew his attention
as an undergraduate at Rice University in Houston. The unbelievable
journey from single egg to fully developed human being captured
his attention in the same way that the journey of stars had
captured his father’s. He thought about becoming a physician.
But the desire to learn more about those mysterious cells won
out and ultimately he earned a Ph.D. in biochemistry from the
University of Washington.
It was while doing a post-doctoral fellowship at Baylor College
of Medicine that Chamberlain found a way to combine the scientist’s
love of discovery and the physician’s love of healing:
he discovered that little was known about the development of
muscle cells and that whatever he learned could eventually make
a difference in the lives of those with muscular dystrophy.
Insofar as there are stars in the research firmament whose
luster transcends the world of laboratories and symposia, Chamberlain
is one. And he is outspoken, albeit quietly. His intense determination
to conquer muscular dystrophy is coupled with an equally intense
frustration at those whose research fervor doesn’t match
his own. “If it were left to the pharmaceutical companies,
there would be no hope for a cure for many of the major diseases
in the world today,” he says firmly. “They look for
a big-time payoff within a few years.”
The payoff he seeks may remain years away, but it’s still
closer than anyone could have imagined even two years ago. In
Chamberlain’s view, the progress he and his team have made
can be largely attributed to the long-term perspective of the
Muscular Dystrophy Association. Indeed, his admiration for the
Association’s modus operandi was one of the factors that
lured the renowned molecular biologist into what has become
his life’s work. Once he became interested in muscle development
in graduate school, he was surprised to discover that the Association
was supporting such ground-level work.
(Above) Chamberlain with graduate student Simone Abmayr
in the lab. |
“This was considered basic research in its purest form,”
he says, “so I was amazed to find out that it was heavily
funded by the Muscular Dystrophy Association. The reason was
that we knew almost nothing about the causes of the muscular
dystrophies (there are more than 15 forms of the disease), so
the organization felt it was important to learn as much as possible
about normal muscle biology in the hope that it would lead to
greater understanding of the muscular dystrophies. Knowing that
they were supporting research that didn’t have an obvious
link to diseases piqued my interest. They’re one of the
few organizations in the world that has been willing to invest
20 or 30 years ahead of time to try to achieve a goal.”
About a million people worldwide suffer from some form of muscular
dystrophy; 20,000 of them are in North America, and two-thirds
are children. The most common form of the disease is caused
by mutations in a large, complex gene that normally produces
dystrophin–a protein critical for maintenance of muscle
tissue. Without dystrophin, children with muscular dystrophy
gradually lose muscle tissue and eventually die by their mid-20s
of heart or respiratory failure.
The next big step will be human clinical trials, expected to
begin within the next year, of a viral vector, developed in
Chamberlain’s lab, that proved capable of long-term delivery
of the dystrophin gene to the muscles of adult mice with Duchenne-like
muscular dystrophy. Duchenne is the most common type of muscular
dystrophy, and the hope is that whatever will remedy the Duchenne
form will also be effective against most other forms of the
disease.
“We have a vector with the potential to deliver a miniature
factory capable of producing normal dystrophin, but which should
not lead to self-destruction of the treated muscle,” says
Chamberlain. “By taking a cold virus known as adenovirus
and removing all the viral genes, which was critical because
they can trigger a person’s natural immunity, we’ve
been able to pack a normal dystrophin gene into the virus.”
But, he says, “the greatest challenge is that we must
find ways to get these viruses to muscles throughout the human
body. And we must show that these new viral vectors can be used
safely, without toxicity or side effects. We also need to know
as early as possible if there are serious drawbacks to the system
we’re developing. If it’s not safe, it’s not
worth spending years to perfect. If it is safe, only then can
one start to ask questions about efficacy.”
There are, in fact, a whole host of questions to be asked.
The relative youth of gene therapy means that its investigative
protocols are often quite different from those for traditional
drug therapy. “For example, we don’t have a single
drug that can be given in pill form to a patient and it will
spread throughout the body,” says Chamberlain. “We
have a very complicated delivery system that’s in the infancy
of its development. Even after we find out if it’s safe
and showing promise for further development, we’ll want
to perfect the ability of the system to produce maximal levels
of the therapeutic protein, and we’ll need to modify the
way the system is put together in order to maximize its ability
to persist for very long periods of time in the human body.”
The initial trials will “be addressing some of the early
questions,” he says. “We’ll be testing our system
by single-site injections in order to ask whether we are getting
a safe uptake of the virus at the site of the injection and
long-term retention in
the muscle. But taking this to the next level and being able
to deliver these type of viruses to all the muscles of the patient
is an enormous challenge. It is going to extend many years beyond
the initial trials.”
But, just like Jerry Lewis, who has been associated with the
Tucson, Arizona-based Muscular Dystrophy Association, now in
its 50th year, since its earliest days, Chamberlain has made
a long-term commitment. So have his sponsors, the National Institutes
of Health (slightly more than half his support comes from the
NIH), the Muscular Dystrophy Association and private donors.
“Today we know muscular dystrophy can be cured,” he
says with the determination of a man who knows his goal and
intends to reach it. “It’s only a question of when.”
You may reach Jeffrey Chamberlain at chamberl@umich.edu
Also:
Sellners
Endow Professorship in Department of Human Genetics
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